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OCR for page 489
Vl
Organic
Solutes
INTRODUCTION
Selection of Agents
.
In selecting agents to be included in the organic contaminants section of
this report, a number of tabulations of organic contaminants detected in
drinking water were examined. From these lists, agents were selected that
have been reported to be present in one or more drinking-water supplies
at relatively high concentrations and for which there were data to suggest
toxicity in man or animals. Also included were several agents that exhibit
a structural relationship to other compounds for which toxicity data were
available and all of the agents listed in the current interim standards, as
well as those specific compounds listed in the Federal Register of
December 24, 1975. A total of 298 volatile organic compounds were
considered and 74 of these were selected for evaluation.
Similar criteria were used to select the organic pesticides for inclusion
In this report. Several additional agents were added after examination of
the usage patterns for all major types of organic pesticides, as well as a
number of agents that were considered to be potential contaminants of
drinking-water supplies because of the large quantities produced. A total
of 55 organic pesticides were selected for evaluation.
489
OCR for page 490
490 DRINKING WATER AND H"LTH
Evaluation of Toxicity
A critical review of the available literature on the toxicology of each
agent (or group of related agents) was carried out as the first stage in the
evaluation. Although the primary focus in these reviews was on
carcinogenesis and other chronic toxic effects, test results and data on
teratogenesis, mutagenesis, reproductive ejects, metabolism, acute
toxicity, and other types of studies were included when available.
Information on the current production, manufacturing methods, and
environmental distribution was included for some pesticides and other
organic compounds.
In the second stage of the evaluation, both the quantity and quality of
the information in each of the critical reviews was considered to
determine whether the data would permit judgments to be made
regarding carcinogenicity or estimation of a maximum no-observed-
adverse-e~ect level.
The hazards of ingesting compounds that were assessed as confinned
or suspected carcinogens were evaluated in terms of dose-related risks, as
described below and in Chapter II. It is recognized that extrapolation of
high-dose animal bioassay data to low-dose human exposures is beset by
limitations, and that it is difficult to reconcile the results of experiments
on animals that may show different target-organ responses, and may
metabolize carcinogens at different rates and by different pathways. Such
risk assessment and extrapolation procedures are further compromised
by the limited information that is available concerning the mechanisms
by which these agents act (e.g., as initiators, promoters, modifiers) and
the almost total lack of data regarding the potentially synergistic and
antagonistic interactions of these agents with each other and with other
environmental agents. Despite these and other uncertainties, the "risk
estimate" approach has been adopted as the basis for analyzing the data
on carcinogenicity rather than the "safety factor" approach.
After a substance had been identified as a carcinogen, the risk to man
was expressed as the probability that cancer would be produced by
continued daily ingestion over a 70 yr lifetime of 1 liter of water
containing a standard quantity (1 ,ug/liter) of the substance in question.
Estimates expressed in this form may then be used to calculate risk due to
the concentrations actually found in drinking-water and the daily
consumption.
To make such estimates from the results of animal feeding studies, two
steps are necessary. The first involves conversion of the standard human
dose to the physiologically equivalent dose in the animal. This was
performed on the basis of relative surface area (details are given in Hoel
OCR for page 491
Organic Solutes 491
et al., 1975, Chapter II). The second step requires use of a risk model
relating dose to eject. The model used for this purpose is
p (~) = I - c,-(A,, + A, ~ + At d' + . . . A'. d')
where P(a) is the lifetime probability that dose d (total daily intake) will
produce cancer, K = the number of events in the carcinogenic process,
and Ao,\~,A2, etc. . . . are nonnegative parameters (see Chapter II). At
low doses, the higher-order terms in d2,a~, etc., may be neglected and
P (d) ~ I _ {,-(A,, + APO ~ A`, + A, d
No representing the background rate. When two or more sets of results of
lifetime animal feeding studies were available, experimental values of
P(a), the fraction of test animals developing cancer, and d, the total daily
dose, were fitted to the equation to determine how many of the terms
Ao,A~d,A2d2, etc., were necessary to give the best fit. Corresponding values
Of Ao,A,, or X0, Al and \2, etc., were used to calculate Pep for the low-dose
of interest, namely the animal dose that was physiologically equivalent to
the standard dose for man. If the animal experiments involved only one
dose level, the Aid term, alone, was used in the calculation. Upper
confidence limits in the estimated low-dose risk were also calculated by
use of maximum likelihood theory (Guess and Crump, 1976, Chapter II),
and these values were tabulated. Since the animal data were obtained
from lifetime feeding studies, the risk estimates calculated from them for
the low-doses that were estimated to be physiologically equivalent to the
human dose were taken to represent the lifetime risks for man. The
background rate, obtained from the cancer incidence in the control
groups of experimental animis and represented by the parameter ho, was
excluded from the tabulated values of P(a), which therefore represent the
incremental risks due to ingestion of the compounds in water.
It was felt that predictions that are risk-related provide a more
meaningful first approximation of hazard than safety-related predictions.
The risk estimate approach may provide unique advantages for other
areas of toxicological evaluations, such as mutagenesis, and it is
recommended that the usefulness of this procedure be evaluated as a new
predictive method in toxicology.
For agents that were not considered to be known or suspected
carcinogens and for which there were adequate toxicity data from
prolonged ingestion studies in man or animals, the more traditional
approach was utilized of combining the maximum dose producing no-
observed-adverse-e~ects with an uncertainty (risk) factor to calculate an
OCR for page 492
492 DRINKING WATER AND H"LTH
ADI (acceptable daily intake). Several alternative terms, other than ADI,
were considered, but it was concluded that the introduction of new terms
might well lead to confusion and that the use of a widely recognized and
generally acceptable term would be preferable for this report. The ADI
has been used previously as an internationally established standard for
the toxicologic evaluation of food additives and contaminants and the
concept is applicable to other ingestion exposure situations. The ADI
represents an empirically derived value that reflects a particular combina-
tion of knowledge and uncertainty concerning the relative risk of a
chemical. The uncertainty factors used to calculate ADI values in this
report represent the level of confidence that was judged to be justified on
the basis of the animal and human toxicity data. All calculations for an
ADI were based on chronic feeding studies, but other considerations,
e.g., mutagenicity, teratogenicity, and lack of sex and strain information,
influenced the choice of the uncertainty factor. ADI values were not
calculated for agents where the data were considered to be inadequate.
Since the calculation of the ADI values is based on the total amount of
a chemical that is ingested, the ADI values calculated in this report do
not represent a safe level for drinking water. However, a suggested no-
anticipated-adverse-e~ect level has been calculated for these chemicals in
drinking water using two hypothetical exposures (where water constitutes
1% and 20~o of the total intake of the agent), and similar calculations can
readily be made for other exposures.
Conclusions
The organic contaminants that have been identified in drinking water
constitute a small percentage of the total organic matter present in water.
Although approximately 9OYo of the volatile organic compounds in
drinking water have been identified and quantified, these represent no
more than logo of the total organic material. Of the nonvolatile organic
compounds comprising the remaining 90~o of the total organic matter in
water, only 5 to logo have been identified. From the 74 nonpesticide
organic compounds and 55 organic pesticides selected for study, 22 have
been identified as known or suspected carcinogens, 46 as having sufficient
toxicity data to permit the calculation of an ADI value or a suggested no-
adverse-effect level for drinking water, 6 as mutagens and 7 as teratogens.
There were 61 agents for which the toxicity data were judged to be
inadequate for establishing any recommendations. (See Tables VI-63 and
64 in "Summary of Organic Solutes.")
It is evident that this effort constitutes only the beginning of a very
large task. However, in preparing these reports and recommendations, an
~_
OCR for page 493
Organic Solutes 493
attempt has been made to use procedures that will enable efforts in the
future to be focused on revisions and additions to the estimates, adding to
and updating, rather than on redoing, the task. Also identified are certain
priorities for the selection of agents to be studied and the research needs
in toxicology and epidemiology to facilitate the evaluation of the
potential health hazards associated with organic agents that are or may
be present in our drinking-water supplies.
PESTICIDES: HERBICIDES
Chloropheno~s
2,4D
Introduction
2,4-D, or 2,4dichlorophenoxyacetic acid, was introduced as a plant
growth-regulator in 1942 (USEPA, 1974b). It is registered in the United
States as an herbicide for control of broadleaf plants and as a plant
growth-regulator. Domestic use of 2,4-D is estimated at 40-50 million
pounds a year, approximately 84% of which is used agriculturally and
about 16% nonagriculturally (mainly for forest brush control).
2,4-D is produced commercially by chlorination of phenol to form 2,4
dichlorophenol, which reacts with monochloroacetic acid to form 2,4D
(USEPA, 1974b). Commercial 2,4-D formulations are generally com-
posed of the salts or esters (ethyl, isopropyl, buty1, amyl, hepty1, octyl,
etc.) of the acid. Analysis of 28 samples of technical 2,4-D by gas
chromatography showed that hexachlorodioxins were present in only one
sample, at less than 10 ppm (Woolson et al., 1972~. The dioxin most likely
to be formed, 2,7-dichlorodibenzo-p-dioxin, was not found. The major
impurity in technical 2,4-D was identified as bis-~2,4dichIorophenox-
y~methane, at 30 ppm (Huston, 1972~.
The solubility of 2,4-D in water is 540 ppm at 20°C; its major
breakdown product, 2,4-dichlorophenol, is soluble at 4,500 ppm
(USEPA, 1974b). The 2,4D salts are in general highly soluble, but the
esters are much less soluble.
2,4D is chemically quite stable, but its esters are rapidly hydrolyzed to
the free acid. Microbial degradation of 2,4-D contributes to its rapid
breakdown (half-time, 1 week) in water (USEPA, 1974b). When exposed
to sunlight or ultraviolet irradiation, aqueous 2,4D solutions decompose
to 2,4-dichlorophenol, 4chlorocatechol, 2-hydroxy-4chlorophenoxy
OCR for page 494
494 DRINKING WATER AND H"LTH
acetic acid, 1,2,4benzene trial, and polymeric humic acids. The overall
breakdown rate of 2,4D in aqueous solution is fairly high, and 2,4-
dichlorophenol is even more photolabile. Most 2,4-D residues are
retained in the soil, where breakdown usually occurs within 6 weeks.
Between 1964 and 1970, only 50 samples of food were found to be
contaminated with 2,4-D; the concentrations detected were 0.021~.16
ppm (USEPA, 1974b). Residues were found in 1% or less of dairy
products, oils, fats and shortening, and fruit, in 1.9% of leafy vegetables,
and in 22.1% of sugar and adjuncts.
2,4D is found in water (Marigold and Schulze, 1969~. Concentrations
as high as 70 ppb have been detected in Oregon streams after aerial
application to forestland (Hiatt, 1976~. 2,4-D was detected in raw water at
0.05 ,ug/liter, in Lafayette, Indiana (USEPA, 1975j). The EPA has set an
interim standard for 2,4-D in finished water of 0.1 mg/liter (USEPA,
1975i).
Metabolism
When 2,4-D with labeled carbon was administered orally to sheep, 96% of
the dose was excreted unchanged in the urine in 72 h, slightly less than
1.4% in the feces (Clark et al., 1964~. When adult sheep and cattle were
fed 2,4-D in the diet for 28 days at up to 2,000 ppm, the kidney contained
the highest and the liver somewhat lower concentrations of 2,4-D and its
breakdown product 2,4-dichlorophenol (Clark et al., 1975~. Withdrawal
from treatment for 7 days resulted in almost complete elimination of 2,4-
D and its major metabolite from the tissues.
In rats that received 1-10 mg of 2,4D, there was almost complete
excretion in the urine and feces in 48 h; at higher doses, some
accumulation occurred in tissues (Khanna and Fang, 1966~.
After subcutaneous injection of 2,4-D and its butyl and isoocty} esters
into mice at 100 mg/kg, the esters were eliminated rapidly, and only 5-
10% of the 2,4-D remained after 1 day (USEPA, 1974b). No 2,4
dichlorophenol was detected in extracts of the treated mice.
In feeding studies of 2,4-D with dairy cows and steers, unchanged 2,4-
D was found only in the urine (Bache et al., 1964a, b; Guteman et al.,
1963a, b; Lisk et al., 1963~. Other studies (Burchfield and Storrs, 1961;
Klingman et al., 1966) demonstrated that 2,4D was eliminated in the
milk of cows maintained in pastures treated with 2,4-D or its butyl or
isooctyl ester.
The pharmacokinetic profile of 2,4D has been determined in five male
human volunteers (Sauerhoff et al., 1976~. After ingestion of a single 5-
mg/kg oral dose, 2,4-D was eliminated from plasma in an apparent first
OCR for page 495
Organic Solutes 495
order process with an average half-life of 11.7 h. All subjects excreted 2,l
D in the urine with an average half-life of 17.7 h, mainly as free 2,4-D
(82.3~o), with a smaller amount excreted as a 2,~D conjugate (12.8~o).
Health Aspects
Observations in Man A 46-yr-old male farmer accidentally ingested a
2,4-D formulation; the dose was estimated to contain 2,4-D at 100
mg/kg, S-ethyldipropylthiocarbamate at 230 mg/kg, and epichlorohy-
drin at 2.3 mg/kg (Berwick, 1970~. The clinical picture was indicative of
2,4-D poisoning with symptoms including fibrillate twitching and
muscular paralysis. Serum glutamic oxalacetic transaminase, glutamic
pyruvic transaminase, lactic dehydrogenase, aldolase, and creatine
phosphate were increased, and both hemoglobinuria and myoglobinuria
were observed. After recovery of the patient, there was also a 4-month
loss of sexual potency.
In testing 2,4-D for possible use in disseminated coccidiomycosis, 18
intravenous doses were administered to a patient over a 33-day period,
with no observed side effect (Seabury, 1963~. The dosage was 15 mg/kg
for the last 12 doses, except that the eighteenth was increased to 37
mg/kg. Following the nineteenth and final dose of 67 mg/kg, the patient
exhibited fibrillary twitching and general hyporeflexia. The patient later
died, apparently owing to the disease.
After a 23-yr-old man used 2,4-D in suicide, the lethal dose was
estimated to be over 90 mg/kg (Nielsen et al., 1965~.
Assouly (1951) is reported to have taken 2,4-D daily at 8 mg/kg for 3
weeks without harmful erects. Data from Dow Chemical Co. (Johnson,
1971) on 220 workers exposed to 2,4-D at 0.43-0.57 mg/kg/day over a
period of 0.5-22 yr showed no significant differences from data on an
unexposed human population.
Observations in Other Species
Acute Elects The acute toxicity of 2,4-D is moderate in a number of
animal species, with LD50 values of 10~541 mg/kg for rats, mice, guinea
pigs, chicks, and dogs (Drill and Hiratzka, 1953; Rowe and Hymas,
1954~. Salts and esters of 2,4-D show an even lower degree of acute
toxicity.
The acute oral toxicity of the major 2,4-D breakdown product 2,4-
dichlorophenol is 580 and 1,625 mg/kg for the rat and the mouse,
respectively (Toxic Substances List, 1974~.
OCR for page 496
496 DRINKING WATER AND H"LTH
Subchronic and Chronic Effects Young adult female rats were given
oral doses of 2,4-D in olive oil at 0, 3, 10, 30, 100, and 300 mg/kg five
times a week for 4 weeks (Rowe and Hymas, 1954~. No adverse effects
were noted at 30 mg/kg and below, but depressed growth rates, liver
pathology, and gastrointestinal irritation occurred at 300 mg/kg. In
another experiment (Rowe and Hymas, 1954), depressed growth, liver
pathology, mortalities, and increased liver/body weight ratios were
observed in rats fed 1,000 ppm 2,4-D for 113 days.
2,4-D was administered orally to dogs at dosage levels of 0, 2, 5, 10, and
20 mg/kg 5 days a week for 13 weeks (Drill and Hiratzka, 1953~. Three of
four animals receiving 20 mg/kg dose died within 49 days. These animals
showed a definite decrease in the percentage of lympocytes in the
peripheral blood. The surviving animals in all groups did not show any
hematological abnormalities.
Dietary levels of 0, 5, 25, 125, 625, and 1,250 ppm technical grade 2,4-D
were fed to female and male Osborne-Mendel rats for 2 yr (Hansen et al.,
1971~. No significant ejects were observed on growth, survival rate,
organ weights, or hematologic parameters. There was also no elevated
incidence of tumors over that seen in controls.
In a parallel study (Hansen et al., 1971), groups of 6-8-month-old
beagle dogs received 0, 10, 50, 100 and 500 ppm of technical 2,4-D for 2
years. No 2,4-D related ejects were noted. None of the lesions observed
in the 30 dogs were believed related to the treatment.
The no-adverse-effect level of 2,4-D in the dog has been established at
8 mg/kg/day (Lehman, 1965~.
Mutagenicity 2,4-D was unable to induce point mutations in four
microbial systems (Andersen et al., 1971) and showed no activity in
Drosophila (Vogel and Chandler, 1974~. Saccharomyces cerevisiae strain
D4 (5 x 106) was treated with 2 ml of an aqueous 2,4-D suspension (trade
name, U46D-Fluid) (Siebert and Lemperle, 1974~. The mitotic gene
conversion frequency of the ade 2 locus was increased fivefold above
control values; that of the try 5 locus was increased sixfold above control
values.
Carcinogenicity Studies on the in vitro and in viva eject of 2,~D on
the growth of Ehrlich ascites tumor in BALB/c mice showed that the
herbicide was inhibitory at 45 mg/kg or more (Walker et al., 1972~. There
was no significant increase in the incidence of tumors in various mouse
strains initially given 2,4-D or its esters at 46.4 mg/kg/day orally on days
7-28 followed by dietary feeding up to 323 ppm for 18 months (USEPA,
1974b). In another study, mice that received 2,4-D orally for their life
OCR for page 497
Organic Solutes 497
span showed no increased incidence of tumor formation (Vettorazzi,
1975b).
A study (Arkhipor and Kozlova, 1974) reported that two rats
developed fibroadenoma and one hemangioma 27-31 months after
receiving one-tenth the LD50 of the amine salt of 2,4-D. Administration
of 0.1 the LD50 dose of the amine salt orally or subcutaneously to mice
produced no tumors after 33 months. The herbicide, however, had a
cocarcinogenic erect in mice when it was applied to the skin with 3-
methylcholanthrene. DNA synthesis was increased, and there was a loss
of cell differentiation in cultured chicken muscle after treatment with
high concentrations of 2,4-D (Haag et al., 1975~.
2~4-Dichlorophenol has not been tested for carcinogenicity alone
(USEPA, 1974b), but it is an initiator for skin carcinogenesis (Boutwell
and Bosch, 1959~.
Reproduction In a three-generation, six-litter Osborne-Mendel rat
reproduction study, no deleterious erects due to technical 2,4-D at
dietary doses of 100 or 500 ppm were observed (Hansen et al., 1971~. At
1,500 ppm, however, 2,4-D, although affecting neither fertility of either
sex nor litter size, sharply reduced the percentage of pups that survived to
weaning and the weights of the weanlings.
Teratogenicity In studies of CD-1 mice, Courtney (cited in EPA,
1974b) found that 2,4-D at 221 mg/kg per day increased fetal mortality,
but produced no cleft palates. Various 2,4-D esters (isopropyl ester at 147
mg/kg/day, n-butyl ester at 155 mg/kg/day, and isooctyl ester at 186
mg/kg/day) had no erect on the incidence of cleft palate or fetal
mortality, but did affect fetal weight. A significant increase in cleft palate
was found, however, after administration of the propylene glycol butyl
ether ester at 195 mg/kg/day.
A statistically significant increase in the proportion of abnormal fetuses
was reported in mice that received maximally tolerated subcutaneous
doses of the isooctyl ester, and two isopropyl esters of 2,4-D (130, 100,
and 94 ,ug/kg, respectively), in dimethyl sulfoxide (DMSO) solution
(Mrak, 1969~. DMSO itself, however, is a teratogen (Caujolle et al., 1967~.
Bage et al. (1973) observed teratogenic and embryotoxic erects in
NMRI mice that received 50- or 110-mg/kg injections of 2,4-D on days
~14 of gestation.
Pregnant rats were treated orally with 2,4-D at 12.5, 25, 50, 75, and 87.5
mg/kg/day (maximal tolerated dose) or equimolar doses of propylene
glycol butyl ether ester of 2,4-D up to 142 mg/kg/day or isooctyl ester of
2,4-D up to 131 mg/kg/day on days ~15 of gestation (Schwetz et al.,
OCR for page 498
498
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OCR for page 499
Organic Solutes 499
1971~. Fetotoxic responses were seen at the high dosages, but teratogenic
ejects were not seen at any dosage. The authors suggested that the no-
adverse effect dosage of 2,4-D (or the molar equivalent, in the case of the
esters) was 25 mg/kg/day.
Prenatal studies on 2,4-D in Wistar rats showed that it induced
fetotoxic ejects and an increased incidence of skeletal anomalies after
single oral doses of 100 150 mg/kg/day on days 6 15 of gestation (Khera
and McKinley, 1972~. At the highest dosage of 150 mg/kg/day, the
isooctyl ester, and butyl ester, and butoxyethynol and dimethylamine
salts of 2,4-D were all associated with significantly increased teratologic
incidence. The butyl and isooctyl esters also tended to decrease fetal
weight. At a lower dosage, 2,4-D and its salts and esters induced no
apparent harmful effects.
Pregnant hamsters received technical 2,4-D (three samples) at 20, 40,
60, and 100 mg/kg/day orally on days 6 10 of gestation (Collins and
Williams, 1971~. Terata were produced occasionally with 2,4-D, and the
fetal viability per litter decreased; but neither eject was clearly dose-
related. The lowest dose causing fetal anomalies with the three technical
2,4-D samples was 60 mg/kg/day.
Conclusions and Recommendations
The acute toxicity of 2,4-D is moderate. No-adverse-effect doses for 2,4-
D were up to 62.5 mg/kg/day and 10 mg/kg/day in rats and dogs,
respectively. Based on these data, an ADI was calculated at 0.0125
mg/kg/day. The available data on subchronic and chronic toxicity and
calculations of ADI are summarized in Table VI- 1.
The acceptable daily intake of 2,4-D has been established at 0.3 mg/kg
by FAD/WHO. On the basis of electron-capture gas chromatography,
the detection limit for 2,4-D in water is 1 ppb.
There are substantial disagreements in the results of subchronic and
chronic toxicity studies with 2,4-D, perhaps reflecting the use of different
formulations or preparations. In view of these deficiencies and the
variability of the results, additional, properly constituted toxicity studies
should be undertaken.
2,4,5-T AND TCDD
Introduction
2,4,5-T, or 2,4,5-trichlorophenoxyacetic acid, was introduced in 1944 as a
translocated, selective herbicide; it is applied after emergence and is
OCR for page 846
846 DRINKING WATER AND H"LTH
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~~~ -~ r- -r~ -~ ~
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Representative terms from entire chapter:
organic solutes
